The antidepressant fluoxetine induces necrosis by energy depletion and mitochondrial calcium overload

Abstract

Selective Serotonin Reuptake Inhibitor antidepressants, such as fluoxetine (Prozac), have been shown to induce cell death in cancer cells, paving the way for their potential use as cancer therapy. These compounds are able to increase cytosolic calcium concentration ([Ca2+]cyt), but the involved mechanisms and their physiological consequences are still not well understood. Here, we show that fluoxetine induces an increase in [Ca2+]cyt by emptying the endoplasmic reticulum (ER) through the translocon, an ER Ca2+ leakage structure. Our data also show that fluoxetine inhibits oxygen consumption and lowers mitochondrial ATP. This latter is essential for Ca2+ reuptake into the ER, and we postulated therefore that the fluoxetine-induced decrease in mitochondrial ATP production results in the emptying of the ER, leading to capacitative calcium entry. Furthermore, Ca2+ quickly accumulated in the mitochondria, leading to mitochondrial Ca2+ overload and cell death. We found that fluoxetine could induce an early necrosis in human peripheral blood lymphocytes and Jurkat cells, and could also induce late apoptosis, especially in the tumor cell line. These results shed light on fluoxetine-induced cell death and its potential use in cancer treatment.

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“…Interestingly, in another study where the effect of fluoxetine was studied on non-GBM cancer cell lines, mitochondrial calcium overload and cell death were explained by a completely different mechanism [127]. The effects were observed after exposure to 100 µM of fluoxetine, a clearly supra-pharmacologic concentration.…”

“…This could reduce ATP production, which is required for maintenance of the low intracellular Ca 2+ concentration. Eventually the increased Ca 2+ load was causing direct damage to the mitochondria and release of pro-apoptotic molecules [127].…”

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“…CaBPs also increased the intracellular Ca 2+ concentration in MCF-7 cells compared to BPs-treated cells ( Figure S16, Supporting Information), which has been documented to be a cause of programmed cell death. [22] Taken together, these results suggested that CaBPs showed enhanced anticancer bioactivity superior to bare BPs owing to intracellular Ca 2+ overload and the stronger pH-responsive degradation in cancer cells.…”

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“…Therefore, it was not possible to correlate the changes in [IP 1 ] to that of intracellular Ca 2+ release or subsequent changes in [Ca 2+ ] i . It is interesting to note that a recent report from Charles et al demonstrated that real-time increases in IP 3 levels could be monitored using confocal microscopy in HeLa cells transfected with a fusion protein made of the Pleckstrin Homology (PH) domain of PLCδ and enhanced green fluorescent protein (eGFP) [42]. The fusion protein binds to phosphatidylinositol 4, 5-bisphosphate (PIP 2 ) and IP 3 and allows the monitoring of IP 3 localization after PIP 2 cleavage regardless of the PLC isoform [42].…”